Most types of molecule and cellular component of animal cells are affected during [blank_start]ageing[blank_end], and different types of animal cells have [blank_start]different lifespans[blank_end].
Cellular ageing is studied using cells from model organisms that have very different lifespans.
Two of the many theories of ageing are the n[blank_start]etwork theory[blank_end], which states that cellular ageing is the result of a [blank_start]combination of processes[blank_end], and the f[blank_start]ree radical theory[blank_end], according to which [blank_start]free radical damage[blank_end] is the cause of [blank_start]molecular and cellular ageing[blank_end].
combination of processes
ree radical theory
free radical damage
molecular and cellular ageing
Genes that confer protection against [blank_start]free radicals[blank_end] and other stresses may have a positive effect against molecular and cellular damage occurring during [blank_start]ageing[blank_end], but will only be selected for by evolution if they also promote [blank_start]reproductory fitness[blank_end].
Vertebrate tissues have a mixture of [blank_start]post-mitotic[blank_end] non-dividing cells, such as [blank_start]neurons[blank_end] and skeletal muscle cells, and [blank_start]dividing[blank_end] cells, such as [blank_start]epithelial cells[blank_end] (and germ cells).
Label the diagram of formation of Reactive Oxygen Species during oxidative phosphorylation at the mitochondria
Free [blank_start]radicals[blank_end] are atoms or molecules that possess [blank_start]unpaired[blank_end] electrons and are therefore very [blank_start]reactive[blank_end].
There are many naturally occurring [blank_start]free radicals[blank_end]; one major source within cells is [blank_start]oxidative phosphorylation[blank_end], which takes place in the inner [blank_start]mitochondrial[blank_end] membrane.
Free radicals cause [blank_start]oxidative[blank_end] damage to all types of molecules and cell organelles.
Particularly: DNA damage - [blank_start]double strand breaks[blank_end] and altered bases/nucleosides, chain reactions of free radical formation in [blank_start]lipid peroxidation[blank_end], damage to amino acids causing changes to [blank_start]activity/conformation[blank_end] of the protein.
double strand breaks
Cellular defences against free radicals have evolved; these are either primary or secondary defences. Primary defences include small-molecule radical [blank_start]scavengers[blank_end], proteins that bind [blank_start]metal ions[blank_end], and [blank_start]antioxidant enzymes[blank_end]. Secondary defences include [blank_start]repair enzymes[blank_end], [blank_start]stress response[blank_end] proteins and [blank_start]protein degradation[blank_end] systems.
[blank_start]Replicative senescence[blank_end] is the irreversible state reached by proliferative cells when they withdraw from the [blank_start]cell cycle[blank_end], and do not undergo any further divisions. It has been studied by measuring [blank_start]population doublings[blank_end] of cells in culture.
Senescent cells exhibit changes in [blank_start]gene expression[blank_end], which may not only affect their function, but may also affect [blank_start]surrounding cells[blank_end]. They also look different from [blank_start]dividing cells[blank_end], being bigger and having larger nuclei.
Several different events can cause cells to become [blank_start]senescent[blank_end]; these include [blank_start]telomere[blank_end] shortening, some types of DNA [blank_start]damage[blank_end], decondensation of [blank_start]chromatin[blank_end], overactivity of some [blank_start]mitogenic stimuli[blank_end] and activation of some [blank_start]oncogenes[blank_end].
[blank_start]Telomeres[blank_end] may be preferentially susceptible to [blank_start]DNA damage[blank_end], and therefore not only trigger [blank_start]replicative senescence[blank_end] due to [blank_start]shortening[blank_end] caused by repeated cell division, but also act as a type of ‘sensor’ of DNA damaging events, such as [blank_start]oxidative stress[blank_end].
[blank_start]Post-mitotic[blank_end] cells such as [blank_start]neurons[blank_end] and skeletal muscle cells exhibit a number of changes during ageing. These changes include [blank_start]mitochondrial damage[blank_end], abnormalities in [blank_start]protein folding[blank_end], protein [blank_start]accumulation[blank_end], and [blank_start]protein[blank_end] glycation.
[blank_start]Mitochondrial[blank_end] function is impaired with age, and genes encoded by [blank_start]mtDNA[blank_end] are particularly vulnerable to [blank_start]oxidative damage[blank_end].
Changes in protein [blank_start]folding[blank_end] and turnover occur with increasing age. perhaps due to problems with [blank_start]chaperones[blank_end] or the protein [blank_start]degradation[blank_end] system. Accumulation of misfolded or [blank_start]damaged[blank_end] proteins therefore often occurs in long-lived cells such as [blank_start]neurons[blank_end]. These can form insoluble [blank_start]aggregates[blank_end] called [blank_start]amyloid[blank_end] fibrils or plaques, causing [blank_start]disease[blank_end].
Interaction of [blank_start]sugars[blank_end] with amino acid residues starts a series of reactions leading to [blank_start]protein glycation[blank_end] and the accumulation of [blank_start]AGEs[blank_end] (Advanced Glycosylation End-products). Long-lived proteins (e.g. [blank_start]extracellular matrix proteins[blank_end]) are particularly susceptible to damage by [blank_start]glycation[blank_end].
extracellular matrix proteins
Both mitotic and post-mitotic cells can be affected by genomic instability.
Many segmental [blank_start]progeroid[blank_end] syndromes in humans are due to [blank_start]mutations[blank_end] in genes encoding proteins that play a role in the detection of [blank_start]DNA damage[blank_end], or DNA [blank_start]repair[blank_end]. This suggests that DNA damage plays a role in [blank_start]normal ageing[blank_end].
A [blank_start]mutation[blank_end] in the gene encoding nuclear A-type lamins has also been found in one [blank_start]progeroid[blank_end] syndrome, [blank_start]HGPS[blank_end]. [blank_start]Nuclear lamins[blank_end] are [blank_start]intermediate filaments proteins[blank_end], which form a structural lattice attached to the inner face of the [blank_start]nuclear envelope[blank_end] and play a role in cell [blank_start]division[blank_end] and gene [blank_start]expression[blank_end].
intermediate filaments proteins
The [blank_start]insulin/IGF-1-like[blank_end] signalling pathway in C. elegans , D. melanogaster and mice affects both [blank_start]stress responses[blank_end] and longevity.
Activation of this pathway in these three laboratory model organisms leads to [blank_start]downregulation[blank_end] of stress response genes and [blank_start]reduces[blank_end] lifespan.
Although an [blank_start]analogous[blank_end] pathway occurs in humans, and affects [blank_start]growth[blank_end] and metabolism, the effects on stress response genes and [blank_start]longevity[blank_end] are not known.
mtDNA is more vulnerable to oxidative damage because:
mtDNA is not complexed with histones, which in nuclear chromatin, offer some protection against oxidative damage
almost all mtDNA is coding DNA, so any mutations that occur may affect gene products
DNA repair is not as efficient in the mitochondria, as not all DNA repair mechanisms take place
mtDNA is just more delicate than nuclear DNA
[blank_start]mtDNA[blank_end] codes for several [blank_start]proteins[blank_end] that are required in the [blank_start]TCA[blank_end] cycle and the [blank_start]electron transport[blank_end] chain. So if mtDNA is damaged by [blank_start]ROS[blank_end], this has huge repercussions on the cell's ability to [blank_start]generate energy[blank_end].
Combined with other age related damage to [blank_start]mitochondria[blank_end] in [blank_start]post-mitotic[blank_end] cells, to the membrane and proteins, this can be a real problem.